While methotrexate has been in clinical use for a number of years as an antitumor agent, the recent introduction of high dose schedules followed by citrovorum factor rescue in the treatment of solid tumors has resulted in renewed interest in this agent, and has revealed that our knowledge of the clinical pharmacology of this and related folate antagonists is still incomplete. Topics of present interest are: 1) the role of the metabolite 7-hydroxymethotrexate in the renal toxicity frequently observed with high dose methotrexate; 2) metabolic handling of the folate antagonist aminopterin when administered at high dose levels.